(i) Field of the Invention
The present invention relates to guanidine derivatives of the general formula
in which A represents a chain of 3-6 optionally substituted C atoms, one of which can be replaced by —N(R′)— or —O—; and R′ represents hydrogen or a substituent; the ring skeleton containing only the two double bonds of the thiazole component; pharmaceutically applicable acid addition salts of basic compounds of formula I, pharmaceutically applicable salts of acid group-containing compounds of formula I with bases, pharmaceutically applicable esters of hydroxy or carboxy group-containing compounds of formula I as well as hydrates or solvates thereof.
Guanidine derivatives of formula I which contain one or more asymmetric center can be present as optically pure enantiomers, as mixtures of enantiomers, such as for example racemates, or optionally as optically pure diastereomers, as mixtures of diastereomers, as diastereomeric racemates or as mixtures of diastereomeric racemates.
The products defined at the outset are partly known and partly novel, and they are characterized by valuable pharmacodynamic properties, acting as neuropeptide FF receptor antagonists.
In a first aspect the present invention relates to the use of the compounds described at the outset of Formula I as well as the salts, esters, hydrates and solvates likewise defined at the outset as neuropeptide FF receptor antagonists or for the preparation of corresponding medicinal products, in particular for the treatment of pain and hyperalgesia, withdrawal syndromes in the case of alcohol, psychotropic and nicotine dependences and for the improvement or elimination of these dependences, for the regulation of insulin secretion, food intake, memory functions, blood pressure, and of the electrolyte and energy balance and for the treatment of urinary incontinence or for the preparation of corresponding medicinal products.
The pains to be treated according to the invention can be chronic, acute, long-lasting or temporary, these pains being able to be of operative, traumatic, or pathological origin; an advantage achieved according to the invention consists in the prevention of opioid tolerance and/or opioid dependence.
(ii) Description of the Related Art
Back in 1985 neuropeptide FF (NPFF; H-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 [99566-27-5]), an octapeptide, and neuropeptide AF (NPAF; H-Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH2 [99588-52-0]), a related octadecapeptide, were discovered as neurotransmitters of the central nervous system in cattle brains (Yang et al., Proc. Natl. Acad. Sci. USA 1985, 82(22), 7757-61) and originally characterized as anti-opioid peptides. The carboxy-terminal amidated neuropeptides were, because of their reactivity with anti-Phe-Met-Arg-Phe-NH2 antiserum, included among the FMRF-amide-like peptides. Both peptides have pain-modulating properties, the octapeptide having greater effectiveness. Both peptides play an important role both in opioid-dependent analgesia and in the development of tolerance to opioids (review article: Roumy and Zajac, Europ. J. Pharm. 1998, 345, 1-11; Panula et al., Prog. Neurobiol. 1996, 48, 461-87). Interestingly, in animal tests, NPFF shows, depending on the nature of the administration, both anti-opioid and pro-opioid actions. Thus NPFF can reverse the acute effects of opioids and an increased concentration in the brain is possibly responsible for the development of opioid tolerance and dependence. In rats, for example, the intracerebroventricular (i.c.v.) administration of NPFF lowers the nociceptive threshold and reduces the analgesia induced by morphine. Administration of NPFF to morphine-tolerant rats causes symptoms of withdrawal phenomena. The analgesic effect of morphine in morphine-tolerant rats was reproduced after i.c.v. injection of anti-NPFF IgG (Lake et al., Neurosci. Lett. 1991, 132, 29-32). Immunoneutralization of NPFF by intrathecally (i.t.) administered anti-NPFF antibodies increase the analgesia caused by endogenous and exogenous opioids. By direct injection of NPFF or NPFF-analogues into the spinal cord (i.t.) a pro-opioid effect with a long-lasting opioid-like analgesia and an increased pain-relieving effect of morphine was obtained (Gouardères et al., Eur. J. Pharmacol. 1993, 237, 73-81; Kontinen and Kaso, Peptides 1995, 16, 973-977).
According to other reports NPFF also appears to play a role in physiological processes such as insulin secretion, regulation of food intake, memory functions, regulation of blood pressure and electrolyte balance (Panula et. al., Prog. Neurobiol. 1996, 48, 461-487).
In various types of mammal, such as humans, rats, mice and cattle, the discovery was reported of a gene, which codes NPFF and NPAF as a common precursor protein, from which the two active peptides are finally split off (Perry et al., FEBS Lett. 1997, 409, 426-30; Vilim et al., Mol. Pharmacol. 1999, 55, 804-11). In humans the gene for this precursor is expressed both peripherally in various organs and in regions of the central nervous system, in particular in the cerebellum (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71), while the expression in rats is restricted exclusively to specific regions of the central nervous system such as the hypothalamus, medulla, and dorsal horn of the spinal cord. On the basis of the demonstration of NPFF in human blood plasma it is presumed, that the peptides are peripherally also responsible for hormone-like effects (Sandblom et al., Peptides 1998, 19, 1165-70).
In tissue samples from humans and rats two G-protein coupled receptors (GPCR), NPFF1 and NPFF2 were identified (Bonini et al., J. Biol. Chem. 2000, 275 (50), 39324-31; Kotani et al., Br. J. Pharmacol. 2001, 133, 138-44), NPFF2 being identical to the receptor HLWAR77 originally described as an orphan (Elshourbagy et al., J. Biol. Chem. 2000, 275 (34), 25965-71). NPFF1 and NPFF2 were able to be characterized as specific receptors with affinities in the nanomolar and subnanomolar regions for the two neuropeptides FF and AF. NPFF binds to NPFF1 with a binding constant Kd=1.13 nM and to NPFF2 with Kd=0.37 nM. The identity of NPFF1 and NPFF2 is around 50%. The comparison of the amino acid sequences with known GPCRs shows a 30-40% similarity with human orexin-1, orexin-2, neuropeptide Y(NPY) Y2, cholecystokinin A, NPY Y1, prolactin-releasing hormone receptor and NPY Y4. The distribution of NPFF1 and NPFF2 in various tissue samples from humans and rats was determined by demonstrating the m-RNA using RT-PCR (reverse transcription-polymerase chain reaction). NPFF1 was demonstrated predominantly in the central nervous system (CNS). By contrast, NPFF2 was found predominantly in the spinal cord. These findings are supported by autoradiographic methods using selective NPFF1 and NPFF2 radioligands (Allard et al., Brain Res. 1989, 500, 169-176; Neuroscience 1992, 49, 106-116; Gouardères et al., Neuroscience 2002 115:2 349-61).
The neuropeptides SF (NPSF, 37 amino acids) and neuropeptide VF (NPVF, octapeptide) described as NPFF-related peptides, both located on the so-called NPVF-gene, bind with comparatively greater affinity and selectivity to the NPFF1 receptor than NPFF and NPAV. The NPVF peptides also block the morphine-induced analgesia in acute and inflammatory pain models more markedly than NPFF and emphasize the importance of the NPVF/FF1 system as part of an endogenous anti-opioid mechanism (Q. Liu et al., J. Biol. Chem. 2002, 276 (40), 36961).
The incidence of functional NPFF1 and NPFF2 receptors in adipocytes and the effect of NPFF and NPAF on key sites of signal transmission in the adipose metabolism suggest that the two peptides, alongside their original pain-modulating effects, could also have an influence on the storage and use of body energy (I. Lefrère et al., J. Biol. Chem. 2002, 277 (42), 39169).
The desamino-Tyr-Phe-Leu-Phe-Gln-Pro-Gln-Arg-NH2 peptide was described as the first NPFF-receptor antagonist counteracting the NPFF effects. After i.c.v. injection this peptide reduced the withdrawal syndromes in the case of morphine dependence (Malin et al., Peptides 1991, 12, 1011-1014). However, this peptide showed no bioavailability whatever in the central nervous system. Optimization of the tripeptide Pro-Gln-Arg-NH2 in a combinative approach led to dansyl-Pro-Gln-Arg-NH2, or dansyl-Pro-Ser-Arg-NH2, both with improved properties for passing through the blood-brain barrier, which, after systemic administration in rats led to an improved antagonistic effect of the anti-opioid symptoms caused by NPFF (Prokai et al. J. Med. Chem. 2001, 44, 1623-1626). The Arg-Tyr-amide peptoid BIBP3226 originally described as an NPY Y1 selective receptor antagonist showed a 10-60 times higher affinity to the human and rat-NPFF1 receptor than to the corresponding NPFF2 receptors (Bonini et al., J. Biol. Chem. 2000, 275 (50), 39324-31). From a series of compounds which originate from the NPY Y1 selective antagonist BIP3226, selective hNPFF1 receptor antagonists were obtained which showed affinities of 40-80 nM (Mollereau et al., Europ. J. Pharmacol. 2002, 45, 245-56).
The two neuropeptide FF analogues 1DME ([D-Tyr1,(Nme)Phe3]NPFF) and Nic-1DME (nicotinoyl-pro-1Dme) showed different pharmacological properties in the mouse tail-flick test, although both compounds bind to NPFF1 and NPFF2 with comparable affinity and selectivity. Both 1DME and Nic-1DME reinforce the morphine analgesia after i.t. and i.p. administration, but Nic-1DME cannot suppress morphine-induced analgesia after i.c.v. and i.p. administration (Quelven et al., Europ. J. Pharmacol. 2002, 449, 91-98).
In WO 02/24192 A1 synthetic NPFF ligands with a peptide structure, based on arginine as the central component, are described.